Obesity is a major risk factor for the development of type 2 diabetes and is genetically determined. A genome wide scan to find obesity and energy metabolism genes was completed last year. 517 polymorphic microsatellite markers (spacing of 6.4 cM) were typed in 382 Pima Indian siblings for obesity (percent body fat) and 220 siblings for energy metabolism (24-h energy expenditure, resting metabolic rate, respiratory quotient, etc.). By sib-pair method, regions with LOD scores greater or equal than 2.0 were found at 11q21-q22 for percent body fat (LOD 2.1) 11q23-q24 for 24-hour energy expenditure (LOD=2.0) and 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0) for 24-hour respiratory quotient. An additional region with evidence for linkage to percent fat was detected by the variance component method at 18q12 (LOD=2.3). Possible candidate genes include the leptin receptor at 1p31 and the agouti signaling protein at 20q11.2. Molecular screening for obesity candidate genes was also undertaken. The gene for glucagon-like peptide receptor (GLP1R), an important gene in the regulation of food intake, was screened. GLP1R is composed of 13 exons and maps to 6p21. In 16 Pima Indians with extremes of percent body fat, only 1 variant was detected, a silent substitution in exon 6 at amino acid 170. The agouti signaling protein (ASIP) is also a candidate gene for obesity. The 3 coding exons of this gene were sequenced in 30 unrelated Pimas and no base substitutions were detected. The newly discovered UCP2 gene maps to 11q13 and 2 polymorphisms in exon 4 and 8 were sequenced in 94 unrelated full-blooded Pima Indians. Weak associations were suggested for the exon 8 variant (deletion/insertion) with metabolic rate (p=0.05 for sleep and p=0.04 for 24-hour). The variant in exon 4 was also associated with sleeping metabolic rate (p=0.02). These results suggest a minor contribution from UCP2 to variation in energy metabolism in Pima Indians. Current studies are underway to screen 2 melanocortin receptor genes (MCR4 and MCR5).